Commentary: Statins, COVID-19, and coronary artery disease: killing two birds with one stone
2020; Elsevier BV; Volume: 113; Linguagem: Inglês
10.1016/j.metabol.2020.154375
ISSN1532-8600
AutoresShiva Ganjali, Vanessa Bianconi, Peter E. Penson, Matteo Pirro, Maciej Banach, Gerald F. Watts, Amirhossein Sahebkar,
Tópico(s)Vitamin C and Antioxidants Research
ResumoAlthough various pharmacologic agents are under active study [[1]Mahase E. Covid-19: what treatments are being investigated?.BMJ. 2020; 368: m1252https://doi.org/10.1136/bmj.m1252Crossref PubMed Scopus (64) Google Scholar], there are currently no effective and evidence-based antiviral drugs or drug combinations against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, namely coronavirus disease 2019 (COVID-19). Therefore, supportive therapy and active treatment of COVID-19 clinical manifestations by using feasible and currently available agents, especially Food and Drug Administration (FDA)-approved drugs, still remains an essential therapeutic approach [2Fajgenbaum D.C. Khor J.S. Gorzewski A. Tamakloe M.A. Powers V. Kakkis J.J. et al.Treatments administered to the first 9152 reported cases of COVID-19: a systematic review.Infect Dis Ther. 2020; : 1-15https://doi.org/10.1007/s40121-020-00303-8Crossref Scopus (38) Google Scholar, 3Bianconi V. Violi F. Fallarino F. Pignatelli P. Sahebkar A. Pirro M. Is acetylsalicylic acid a safe and potentially useful choice for adult patients with COVID-19?.Drugs. 2020; 23: 1-14https://doi.org/10.1007/s40265-020-01365-1Crossref Scopus (76) Google Scholar, 4Zahedipour F. Hosseini S.A. Sathyapalan T. Majeed M. Jamialahmadi T. Al-Rasadi K. et al.Potential effects of curcumin in the treatment of COVID-19 infection.Phytother Res. 2020; 10 (1002/ptr.6738)https://doi.org/10.1002/ptr.6738Crossref Scopus (229) Google Scholar]. To this regard, great interest has risen with respect to the potential beneficial effects against COVID-19 of drugs that are currently used for cardiovascular prevention [[3]Bianconi V. Violi F. Fallarino F. Pignatelli P. Sahebkar A. Pirro M. Is acetylsalicylic acid a safe and potentially useful choice for adult patients with COVID-19?.Drugs. 2020; 23: 1-14https://doi.org/10.1007/s40265-020-01365-1Crossref Scopus (76) Google Scholar,[5]Bikdeli B. Madhavan M.V. Jimenez D. Chuich T. Dreyfus I. Driggin E. et al.COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review.J Am Coll Cardiol. 2020; 75: 2950-2973https://doi.org/10.1016/j.jacc.2020.04.031Crossref PubMed Scopus (2161) Google Scholar]. Indeed, although the main clinical manifestations of COVID-19 involve the respiratory system, an increased risk of cardiovascular complications, including myocarditis, cardiac arrhythmias, and arterial and venous thrombosis, has been reported in COVID-19 patients [6Inciardi R.M. Lupi L. Zaccone G. Italia L. Raffo M. Tomasoni D. et al.Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; 5: 1-6https://doi.org/10.1001/jamacardio.2020.1096Crossref Scopus (1283) Google Scholar, 7Guo T. Fan Y. Chen M. Wu X. Zhang L. He T. et al.Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; 5: 1-8https://doi.org/10.1001/jamacardio.2020.1017Crossref Scopus (2835) Google Scholar, 8Madjid M. Safavi-Naeini P. Solomon S.D. Vardeny O. Potential effects of coronaviruses on the cardiovascular system: a review.JAMA Cardiol. 2020; https://doi.org/10.1001/jamacardio.2020.1286Crossref PubMed Scopus (1298) Google Scholar]. In addition, underlying cardiovascular diseases (CVDs) and/or cardiovascular risk factors (e.g., smoking, diabetes, obesity) have been associated with an increased risk of severe clinical complications and death in COVID-19 patients [6Inciardi R.M. Lupi L. Zaccone G. Italia L. Raffo M. Tomasoni D. et al.Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; 5: 1-6https://doi.org/10.1001/jamacardio.2020.1096Crossref Scopus (1283) Google Scholar, 7Guo T. Fan Y. Chen M. Wu X. Zhang L. He T. et al.Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; 5: 1-8https://doi.org/10.1001/jamacardio.2020.1017Crossref Scopus (2835) Google Scholar, 8Madjid M. Safavi-Naeini P. Solomon S.D. Vardeny O. Potential effects of coronaviruses on the cardiovascular system: a review.JAMA Cardiol. 2020; https://doi.org/10.1001/jamacardio.2020.1286Crossref PubMed Scopus (1298) Google Scholar, 9American College of Cardiology COVID-19 clinical guidance for the cardiovascular care team.https://www.acc.org/latest-in-cardiology/features/~/media/Non-Clinical/Files-PDFs-Excel-MS-Word-etc/2020/02/S20028-ACC-Clinical-Bulletin-Coronavirus.pdfDate: 2020Date accessed: August 15, 2020Google Scholar, 10Palaiodimos L. Kokkinidis D.G. Li W. Karamanis D. Ognibene J. Arora S. et al.Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York.Metabolism. 2020; 108: 154262https://doi.org/10.1016/j.metabol.2020.154262Abstract Full Text Full Text PDF PubMed Scopus (576) Google Scholar, 11Hill M.A. Mantzoros C. Sowers J.R. Commentary: COVID-19 in patients with diabetes.Metabolism. 2020; 107: 154217https://doi.org/10.1016/j.metabol.2020.154217Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 12European Society of Cardiology ESC guidance for the diagnosis and management of CV disease during the COVID-19 pandemic.https://www.escardio.org/Education/COVID-19-and-Cardiology/ESC-COVID-19-GuidanceDate: 2020Date accessed: August 15, 2020Google Scholar]. Whether statins may be re-purposed to treat COVID-19 patients is a matter of debate. There are several points that are worthy of being considered in support of possible beneficial effects of statins against COVID-19. First, statins are widespread, available, low-cost, and safe cholesterol-lowering drugs, that have been extensively demonstrated to reduce significantly CVD risk [[13]Johnston T.P. Korolenko T.A. Pirro M. Sahebkar A. Preventing cardiovascular heart disease: promising nutraceutical and non-nutraceutical treatments for cholesterol management.Pharmacol Res. 2017; 120: 219-225https://doi.org/10.1016/j.phrs.2017.04.008Crossref PubMed Scopus (88) Google Scholar,[14]Borén J. Chapman M.J. Krauss R.M. Packard C.J. Bentzon J.F. Binder C.J. et al.Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European atherosclerosis society consensus panel.Eur Heart J. 2020; 41: 2313-2330https://doi.org/10.1093/eurheartj/ehz962Crossref PubMed Scopus (701) Google Scholar]. Each mmol/l reduction in LDL-cholesterol (LDL-C) reduces the risk of major cardiovascular events by about one quarter for each year statin therapy is continued [[13]Johnston T.P. Korolenko T.A. Pirro M. Sahebkar A. Preventing cardiovascular heart disease: promising nutraceutical and non-nutraceutical treatments for cholesterol management.Pharmacol Res. 2017; 120: 219-225https://doi.org/10.1016/j.phrs.2017.04.008Crossref PubMed Scopus (88) Google Scholar,[14]Borén J. Chapman M.J. Krauss R.M. Packard C.J. Bentzon J.F. Binder C.J. et al.Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European atherosclerosis society consensus panel.Eur Heart J. 2020; 41: 2313-2330https://doi.org/10.1093/eurheartj/ehz962Crossref PubMed Scopus (701) Google Scholar]. Therefore, it is likely that statins may also mitigate CVD risk in COVID-19 patients. Second, due to their cholesterol-lowering activity and their pleiotropic effects, statins can inhibit inflammation, immune response, and oxidative stress [15Liberale L. Carbone F. Montecucco F. Sahebkar A. Statins reduce vascular inflammation in atherogenesis: a review of underlying molecular mechanisms.Int J Biochem Cell Biol. 2020; 122https://doi.org/10.1016/j.biocel.2020.105735Crossref PubMed Scopus (47) Google Scholar, 16Chruściel P. Sahebkar A. Rembek-Wieliczko M. et al.Impact of statin therapy on plasma adiponectin concentrations: a systematic review and meta-analysis of 43 randomized controlled trial arms.Atherosclerosis. 2016; 253: 194-208https://doi.org/10.1016/j.atherosclerosis.2016.07.897Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 17Parizadeh S.M.R. Azarpazhooh M.R. Moohebati M. Nematy M. Ghayour-Mobarhan M. Tavallaie S. et al.Simvastatin therapy reduces prooxidant-antioxidant balance: results of a placebo-controlled cross-over trial.Lipids. 2011; 46: 333-340https://doi.org/10.1007/s11745-010-3517-xCrossref PubMed Scopus (138) Google Scholar], exert direct antiviral effects [[18]Gorabi A.M. Kiaie N. Bianconi V. Jamialahmadi T. Al-Rasadi K. Johnston T.P. et al.Antiviral effects of statins.Prog Lipid Res. 2020; 101054https://doi.org/10.1016/j.plipres.2020.101054Crossref Scopus (45) Google Scholar], improve endothelial function [19Gorabi A.M. Kiaie N. Pirro M. Bianconi V. Jamialahmadi T. Sahebkar A. Effects of statins on the biological features of mesenchymal stem cells and therapeutic implications.Heart Fail Rev. 2020; https://doi.org/10.1007/s10741-020-09929-9Crossref Scopus (36) Google Scholar, 20Ii M. Losordo D.W. Statins and the endothelium.Vascul Pharmacol. 2007; 46: 1-9https://doi.org/10.1016/j.vph.2006.06.012Crossref PubMed Scopus (118) Google Scholar, 21Bianconi V. Sahebkar A. Kovanen P. Bagaglia F. Ricciuti B. Calabrò P. et al.Endothelial and cardiac progenitor cells for cardiovascular repair: a controversial paradigm in cell therapy.Pharmacol Ther. 2018; 181: 156-168https://doi.org/10.1016/j.pharmthera.2017.08.004Crossref PubMed Scopus (101) Google Scholar], and regulate hemostasis [[22]Bianconi V. Sahebkar A. Banach M. Pirro M. Statins, haemostatic factors and thrombotic risk.Curr Opin Cardiol. 2017; 32: 460-466https://doi.org/10.1097/HCO.0000000000000397Crossref PubMed Scopus (23) Google Scholar,[23]Sahebkar A. Serban C. Mikhailidis D.P. Undas A. Lip G.Y.H. Muntner P. et al.Association between statin use and plasma d-dimer levels: a systematic review and meta-analysis of randomised controlled trials.Thromb Haemost. 2015; 114: 546-557https://doi.org/10.1160/TH14-11-0937Crossref PubMed Scopus (139) Google Scholar], potentially reducing the incidence of severe clinical manifestations and improving prognosis in COVID-19 patients. This latter point will be discussed in more depth in the following text. Statins may conceivably protect against inflammation by controlling cytokine overexpression and modulating immune responses [[15]Liberale L. Carbone F. Montecucco F. Sahebkar A. Statins reduce vascular inflammation in atherogenesis: a review of underlying molecular mechanisms.Int J Biochem Cell Biol. 2020; 122https://doi.org/10.1016/j.biocel.2020.105735Crossref PubMed Scopus (47) Google Scholar,[16]Chruściel P. Sahebkar A. Rembek-Wieliczko M. et al.Impact of statin therapy on plasma adiponectin concentrations: a systematic review and meta-analysis of 43 randomized controlled trial arms.Atherosclerosis. 2016; 253: 194-208https://doi.org/10.1016/j.atherosclerosis.2016.07.897Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar], thereby potentially preventing the development of acute distress respiratory syndrome (ARDS) and reducing the incidence of cardiovascular complications in COVID-19 patients. Indeed, statins have been shown to directly inhibit nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) (Fig. 1), which is a crucial mediator of inflammatory responses during infections, including those caused by coronaviruses [[24]DeDiego M.L. Nieto-Torres J.L. Regla-Nava J.A. Jimenez-Guardeño J.M. Fernandez-Delgado R. Fett C. et al.Inhibition of NF-κB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival.J Virol. 2014; 88: 913-924https://doi.org/10.1128/JVI.02576-13Crossref PubMed Scopus (314) Google Scholar]. In addition, they have been reported to negatively regulate the expression of toll-like receptor-4 (TLR4) and consequent activation of the TLR4-myeloid differentiation primary response (MYD)88-NF-kB signaling pathway, which plays a critical role in the recognition of pathogens and induction of the innate immune response against viral infections [[25]Yang S.S. Li R. Qu X. Fang W. Quan Z. Atorvastatin decreases toll-like receptor 4 expression and downstream signaling in human monocytic leukemia cells.Cell Immunol. 2012; 279: 96-102https://doi.org/10.1016/j.cellimm.2012.09.008Crossref PubMed Scopus (23) Google Scholar,[26]Sheahan T. Morrison T.E. Funkhouser W. Uematsu S. Akira S. Baric R.S. et al.MyD88 is required for protection from lethal infection with a mouse-adapted SARS-CoV.PLoS Pathog. 2008; 4e1000240https://doi.org/10.1371/journal.ppat.1000240Crossref PubMed Scopus (173) Google Scholar]. By counteracting cytokine storm statins may reduce the risk of myocardial injury and myocarditis in acute phases of COVID-19 [[27]Radenkovic D. Chawla S. Pirro M. Sahebkar A. Banach M. Cholesterol in relation to COVID-19: should we care about it?.J Clin Med. 2020; 9: 1909https://doi.org/10.3390/jcm9061909Crossref Scopus (99) Google Scholar]. In addition, statin-mediated anti-inflammatory effects may also promote stabilization of atherosclerotic plaques, thereby protecting from the occurrence of plaque rupture and cardiovascular events [[8]Madjid M. Safavi-Naeini P. Solomon S.D. Vardeny O. Potential effects of coronaviruses on the cardiovascular system: a review.JAMA Cardiol. 2020; https://doi.org/10.1001/jamacardio.2020.1286Crossref PubMed Scopus (1298) Google Scholar]. These effects provide an argument in support of statin continuation, even at high doses, for mitigating cardiovascular risk in the acute phases of COVID-19, especially in patients with manifest atherosclerotic CVD or CVD risk factors. Indeed, COVID-19-driven inflammation might promote atherosclerotic plaque instability [[27]Radenkovic D. Chawla S. Pirro M. Sahebkar A. Banach M. Cholesterol in relation to COVID-19: should we care about it?.J Clin Med. 2020; 9: 1909https://doi.org/10.3390/jcm9061909Crossref Scopus (99) Google Scholar]. In addition, although statin-mediated stabilization of atherosclerotic plaques is known to be time-dependent, there are reports showing that some modulation of inflammation and some reduction of plaque remodelling may be obtained also after a short period of treatment with high doses of statins [[28]Sposito A.C. Chapman M.J. Statin therapy in acute coronary syndromes: mechanistic insight into clinical benefit.Arterioscler Thromb Vasc Biol. 2002; 22: 1524-1534https://doi.org/10.1161/01.atv.0000032033.39301.6aCrossref PubMed Scopus (0) Google Scholar,[29]Della-Morte D. Moussa I. Elkind M.S. Sacco R.L. Rundek T. The short-term effect of atorvastatin on carotid plaque morphology assessed by computer-assisted gray-scale densitometry: a pilot study.Neurol Res. 2011; 33: 991-994https://doi.org/10.1179/1743132811Y.0000000039Crossref PubMed Scopus (33) Google Scholar]. However, it should be emphasized that they are currently lacking clinical studies showing a significant impact of statin therapy in reduction of incident cardiovascular events in COVID-19 patients. Statins can exert some direct antiviral activity [[18]Gorabi A.M. Kiaie N. Bianconi V. Jamialahmadi T. Al-Rasadi K. Johnston T.P. et al.Antiviral effects of statins.Prog Lipid Res. 2020; 101054https://doi.org/10.1016/j.plipres.2020.101054Crossref Scopus (45) Google Scholar,[30]Mehrbod P. Omar A.R. Hair-Bejo M. Haghani A. Ideris A. Mechanisms of action and efficacy of statins against influenza.Biomed Res Int. 2014; 2014: 872370https://doi.org/10.1155/2014/872370Crossref PubMed Scopus (67) Google Scholar]. By inhibiting cholesterol synthesis, they can reduce the intracellular availability of a crucial compound for the viral cell cycle [[31]Gordon D. Statins may be a key therapeutic for Covid-19.Med Hypotheses. 2020; 144: 110001https://doi.org/10.1016/j.mehy.2020.110001Crossref PubMed Scopus (9) Google Scholar]. Indeed, the presence of cholesterol-rich subdomains on the plasma membrane of host cells, namely lipid rafts, is crucial for viral fusion and entry [[18]Gorabi A.M. Kiaie N. Bianconi V. Jamialahmadi T. Al-Rasadi K. Johnston T.P. et al.Antiviral effects of statins.Prog Lipid Res. 2020; 101054https://doi.org/10.1016/j.plipres.2020.101054Crossref Scopus (45) Google Scholar,[30]Mehrbod P. Omar A.R. Hair-Bejo M. Haghani A. Ideris A. Mechanisms of action and efficacy of statins against influenza.Biomed Res Int. 2014; 2014: 872370https://doi.org/10.1155/2014/872370Crossref PubMed Scopus (67) Google Scholar]. Furthermore, through cholesterol-dependent mechanisms, statins can inhibit the isoprenylation of different proteins (e.g., RhoA, Rac, and Cdc42), which are critical downstream molecules regulating viral cell cycle [[18]Gorabi A.M. Kiaie N. Bianconi V. Jamialahmadi T. Al-Rasadi K. Johnston T.P. et al.Antiviral effects of statins.Prog Lipid Res. 2020; 101054https://doi.org/10.1016/j.plipres.2020.101054Crossref Scopus (45) Google Scholar,[30]Mehrbod P. Omar A.R. Hair-Bejo M. Haghani A. Ideris A. Mechanisms of action and efficacy of statins against influenza.Biomed Res Int. 2014; 2014: 872370https://doi.org/10.1155/2014/872370Crossref PubMed Scopus (67) Google Scholar]. To date, a number of observational studies have suggested that statin therapy can reduce the risk of various severe complications and mortality in patients admitted with Middle East respiratory syndrome coronavirus (MERS-CoV) infection and influenza [32Frost F.J. Petersen H. Tollestrup K. Skipper B. Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins.Chest. 2007; 131: 1006-1012https://doi.org/10.1378/chest.06-1997Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 33Vandermeer M.L. Thomas A.R. Kamimoto L. Reingold A. Gershman K. Meek J. et al.Association between use of statins and mortality among patients hospitalized with laboratory-confirmed influenza virus infections: a multistate study.J Infect Dis. 2012; 205: 13-19https://doi.org/10.1093/infdis/jir695Crossref PubMed Scopus (176) Google Scholar, 34Yuan S. Statins may decrease the fatality rate of Middle East respiratory syndrome infection.mBio. 2015; 6: e01120https://doi.org/10.1128/mBio.01120-15Crossref PubMed Scopus (75) Google Scholar, 35Fedson D.S. Statin protection against influenza and COPD mortality.Chest. 2007; 132: 1406-1407https://doi.org/10.1378/chest.07-0992Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. Therefore, it is possible that the beneficial effects of statin therapy as an add-on treatment in viral infections could be extended to COVID-19. To this regard, it should be considered that a peculiar antiviral mechanism of action of statins against COVID-19 might consist of inhibition of SARS-CoV-2 entry into host cells due to the binding of its main protease [[36]Reiner Ž. Hatamipour M. Banach M. Pirro M. Al-Rasadi K. Jamialahmadi T. et al.Statins and the COVID-19 main protease: in silico evidence on direct interaction.Arch Med Sci. 2020; 16: 490-496https://doi.org/10.5114/aoms.2020.94655Crossref PubMed Scopus (203) Google Scholar]. Nonetheless, whether statin therapy may reduce the risk of SARS-CoV-2 infection still needs to be investigated. Statins have well-known protective effects against endothelial dysfunction and injury [19Gorabi A.M. Kiaie N. Pirro M. Bianconi V. Jamialahmadi T. Sahebkar A. Effects of statins on the biological features of mesenchymal stem cells and therapeutic implications.Heart Fail Rev. 2020; https://doi.org/10.1007/s10741-020-09929-9Crossref Scopus (36) Google Scholar, 20Ii M. Losordo D.W. Statins and the endothelium.Vascul Pharmacol. 2007; 46: 1-9https://doi.org/10.1016/j.vph.2006.06.012Crossref PubMed Scopus (118) Google Scholar, 21Bianconi V. Sahebkar A. Kovanen P. Bagaglia F. Ricciuti B. Calabrò P. et al.Endothelial and cardiac progenitor cells for cardiovascular repair: a controversial paradigm in cell therapy.Pharmacol Ther. 2018; 181: 156-168https://doi.org/10.1016/j.pharmthera.2017.08.004Crossref PubMed Scopus (101) Google Scholar]. Due to their ability to upregulate ACE2 signaling pathways via epigenetic histone modifications, statins might exert some beneficial effects in terms of endothelial protection in the supportive therapy of COVID-19 patients [[37]Tikoo K. Patel G. Kumar S. Karpe P.A. Sanghavi M. Malek V. et al.Tissue specific up regulation of ACE2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications.Biochem Pharmacol. 2015; 93: 343-351https://doi.org/10.1016/j.bcp.2014.11.013Crossref PubMed Scopus (140) Google Scholar]. Indeed, high levels of ACE2 on pulmonary endothelium have been associated with reduced severity of ARDS [[38]Wösten-van Asperen R.M. Bos A.P. Bem R.A. Dierdorp B.S. Dekker T. van Goor H. et al.Imbalance between pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in acute respiratory distress syndrome.Pediatr Crit Care Med. 2013; 14 (e41): e438https://doi.org/10.1097/PCC.0b013e3182a55735Crossref PubMed Scopus (49) Google Scholar]. In addition, by promoting endothelial repair statins might counteract SARS-CoV-2-induced endothelitis in lungs as a direct consequence of both infection of endothelial cells and the host inflammatory response [[39]Varga Z. Flammer A.J. Steiger P. Haberecker M. Andermatt R. Zinkernagel A.S. et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395: 1417-1418https://doi.org/10.1016/S0140-6736(20)30937-5Abstract Full Text Full Text PDF PubMed Scopus (4433) Google Scholar,[40]Ackermann M. Verleden S.E. Kuehnel M. Haverich A. Welte T. Laenger F. et al.Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.N Engl J Med. 2020; 383: 120-128https://doi.org/10.1056/NEJMoa2015432Crossref PubMed Scopus (3795) Google Scholar], thereby potentially accelerating recovery from ARDS. By inhibiting the activation of coagulation cascade and platelet function as well as increasing fibrinolytic activity, statins can exert antithrombotic effects [[22]Bianconi V. Sahebkar A. Banach M. Pirro M. Statins, haemostatic factors and thrombotic risk.Curr Opin Cardiol. 2017; 32: 460-466https://doi.org/10.1097/HCO.0000000000000397Crossref PubMed Scopus (23) Google Scholar] (Fig. 2). Specifically, different statins have been shown to directly interfere with tissue factor expression, thrombin generation, fibrinogen cleavage, factor V and factor XIII activation, endothelial thrombomodulin expression, and platelet activation [[22]Bianconi V. Sahebkar A. Banach M. Pirro M. Statins, haemostatic factors and thrombotic risk.Curr Opin Cardiol. 2017; 32: 460-466https://doi.org/10.1097/HCO.0000000000000397Crossref PubMed Scopus (23) Google Scholar]. In addition, some inhibitory activity of statins on thrombus formation has been ascribed to their ability to modulate endothelial function and inflammatory response [[22]Bianconi V. Sahebkar A. Banach M. Pirro M. Statins, haemostatic factors and thrombotic risk.Curr Opin Cardiol. 2017; 32: 460-466https://doi.org/10.1097/HCO.0000000000000397Crossref PubMed Scopus (23) Google Scholar] (Fig. 2). Arterial and venous thromboembolic events have been described as typical clinical features of severe COVID-19 [6Inciardi R.M. Lupi L. Zaccone G. Italia L. Raffo M. Tomasoni D. et al.Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; 5: 1-6https://doi.org/10.1001/jamacardio.2020.1096Crossref Scopus (1283) Google Scholar, 7Guo T. Fan Y. Chen M. Wu X. Zhang L. He T. et al.Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; 5: 1-8https://doi.org/10.1001/jamacardio.2020.1017Crossref Scopus (2835) Google Scholar, 8Madjid M. Safavi-Naeini P. Solomon S.D. Vardeny O. Potential effects of coronaviruses on the cardiovascular system: a review.JAMA Cardiol. 2020; https://doi.org/10.1001/jamacardio.2020.1286Crossref PubMed Scopus (1298) Google Scholar]. Therefore, albeit being still not proved, it is plausible that statins might be useful to improve clinical outcomes of COVID-19 by reducing the incidence of COVID-19-related coagulopathy. To date, most of available data from clinical studies support the protective effect of statins against SARS-CoV-2 infection. Indeed, a number of retrospective studies have shown lower inflammatory parameters, decreased incidence of severe clinical manifestations or reduced mortality rates in COVID-19 patients under statin treatment as compared to those not taking statins [[41]Zhang X.J. Qin J.J. Cheng X. Shen L. Zhao Y.C. Yuan Y. et al.In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19.Cell Metab. 2020; 32 (e4): 176-187https://doi.org/10.1016/j.cmet.2020.06.015Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar,[42]Rodriguez-Nava G. Trelles-Garcia D.P. Yanez-Bello M.A. Chung C.W. Trelles-Garcia V.P. Friedman H.J. Atorvastatin associated with decreased hazard for death in COVID-19 patients admitted to an ICU: a retrospective cohort study.Crit Care. 2020; 24: 429https://doi.org/10.1186/s13054-020-03154-4Crossref PubMed Scopus (79) Google Scholar]. However, consistent evidence from prospective studies is not currently available. In addition, two recent meta-analyses of observational studies exploring the impact of statin therapy on COVID-19 outcomes have reported contrasting results [[43]Kow C.S. Hasan S.S. Meta-analysis of effect of statins in patients with COVID-19.Am J Cardiol. 2020; S0002–9149: 30823-30827https://doi.org/10.1016/j.amjcard.2020.08.004Abstract Full Text Full Text PDF Scopus (120) Google Scholar,[44]Hariyanto T.I. Kurniawan A. Statin therapy did not improve the in-hospital outcome of coronavirus disease 2019 (COVID-19) infection.Diabetes Metab Syndr. 2020; https://doi.org/10.1016/j.dsx.2020.08.023Crossref Scopus (64) Google Scholar]. Therefore, clinical trials investigating this issue are eagerly awaited. Against the hypothesis of a clinical benefit of statin use in COVID-19 patients, some safety concerns need to be taken into account. The main doubt about the beneficial effects of statins as add-on therapy in COVID-19 may be raised when considering the possible detrimental impact of reduced low-density lipoprotein (LDL) cholesterol levels on COVID-19 prognosis, as suggested by some retrospective studies [[45]Fan J. Wang H. Ye G. Cao X. Xu X. Tan W. et al.Letter to the editor: low-density lipoprotein is a potential predictor of poor prognosis in patients with coronavirus disease 2019.Metabolism. 2020; 107: 154243https://doi.org/10.1016/j.metabol.2020.154243Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar,[46]Hu X. Chen D. Wu L. He G. Ye W. Low serum cholesterol level among patients with COVID-19 infection in Wenzhou. China, Lancet2020https://doi.org/10.2139/ssrn.3544826Crossref Google Scholar]. However, reverse causality (i.e., viral infection as a cause of LDL cholesterol reduction) instead of causality (i.e., LDL cholesterol reduction as a factor promoting viral infection) might explain the association between LDL cholesterol and severe COVID-19 manifestations [[47]Pirro M, Bianconi V, Sahebkar A. Cholesterol and cholesterol-lowering in COVID-19: why we should not let our guard down. BMJ, https://www.bmj.com/content/368/bmj.m1182/rr-18, 2020 [accessed 15 August 2020].Google Scholar]. This could distract from refuting the potential benefits of statin treatment in this clinical setting. Additional safety concerns may be raised considering the ability of statins to upregulate the expression of angiotensin-converting enzyme 2 (ACE2), which mediates SARS-CoV-2 entry into host cells [[37]Tikoo K. Patel G. Kumar S. Karpe P.A. Sanghavi M. Malek V. et al.Tissue specific up regulation of ACE2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications.Biochem Pharmacol. 2015; 93: 343-351https://doi.org/10.1016/j.bcp.2014.11.013Crossref PubMed Scopus (140) Google Scholar,[48]Lima Martínez M.M. Contreras M.A. Marín W. D'Marco L. Statins in COVID-19: is there any foundation?.Clin Investig Arterioscler. 2020; S0214-9168 (2): 30063https://doi.org/10.1016/j.arteri.2020.06.003Google Scholar]. However, such an effect may be clinically not significant if we assume that viral load is not necessarily related to the disease severity. Moreover, soluble ACE2 may bind to SARS-CoV-2, preventing it from fusion with the membrane of host cells and, therefore, inhibiting viral replication [[48]Lima Martínez M.M. Contreras M.A. Marín W. D'Marco L. Statins in COVID-19: is there any foundation?.Clin Investig Arterioscler. 2020; S0214-9168 (2): 30063https://doi.org/10.1016/j.arteri.2020.06.003Google Scholar]. Another issue is represented by the risk of statin-related myotoxicity and hepatotoxity, which may be increased by drug-to-drug interactions between statins and antiviral, antiretroviral, antiparasitic, and antirheumatic drugs as well as antibiotics (mainly macrolides) that may be concomitantly administered to COVID-19 patients [[49]Banach M. Penson P.E. Fras Z. Vrablik M. Pella D. Reiner Ž. et al.Brief recommendations on the management of adult patients with familial hypercholesterolemia during the COVID-19 pandemic.Pharmacol Res. 2020; 158: 104891https://doi.org/10.1016/j.phrs.2020.104891Crossref PubMed Scopus (56) Google Scholar]. In some cases, either discontinuation of statin therapy or continuation with caution and at lower doses is possible options [[49]Banach M. Penson P.E. Fras Z. Vrablik M. Pella D. Reiner Ž. et al.Brief recommendations on the management of adult patients with familial hypercholesterolemia during the COVID-19 pandemic.Pharmacol Res. 2020; 158: 104891https://doi.org/10.1016/j.phrs.2020.104891Crossref PubMed Scopus (56) Google Scholar]. Nonetheless, when statin discontinuation is required, other lipid-lowering therapies could be considered, especially in patients at high CVD risk, which are more prone to undergo COVID-19 complications [[49]Banach M. Penson P.E. Fras Z. Vrablik M. Pella D. Reiner Ž. et al.Brief recommendations on the management of adult patients with familial hypercholesterolemia during the COVID-19 pandemic.Pharmacol Res. 2020; 158: 104891https://doi.org/10.1016/j.phrs.2020.104891Crossref PubMed Scopus (56) Google Scholar,[50]Katsiki N. Banach M. Mikhailidis D.P. Lipid-lowering therapy and renin-angiotensin-aldosterone system inhibitors in the era of the COVID-19 pandemic.Arch Med Sci. 2020; 16: 485-489https://doi.org/10.5114/aoms.2020.94503Crossref PubMed Scopus (69) Google Scholar]. An additional reason for caution about statin therapy in COVID-19 patients may be the possible statin-mediated increase of lipoprotein(a), which is known to exert an anti-fibrinolytic activity by controlling the activity of plasminogen activators [[51]Edelberg J.M. Pizzo S.V. Lipoprotein (a) in the regulation of fibrinolysis.J Atheroscler Thromb. 1995; 2: S5-S7https://doi.org/10.5551/jat1994.2.supplement1_s5Crossref PubMed Google Scholar]. However, it should be emphasized that statin-mediated increasing effect on lipoprotein(a) is not consistent and in some cases may be not significant [[52]Willeit P. Ridker P.M. Nestel P.J. Simes J. Tonkin A.M. Pedersen T.R. et al.Baseline and on-statin treatment lipoprotein (a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.Lancet. 2018; 392: 1311-1320https://doi.org/10.1016/S0140-6736(18)31652-0Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar,[53]Yahya R. Berk K. Verhoeven A. Bos S. Van Der Zee L. Touw J. et al.Statin treatment increases lipoprotein (a) levels in subjects with low molecular weight apolipoprotein (a) phenotype.Atherosclerosis. 2019; 289: 201-205https://doi.org/10.1016/j.atherosclerosis.2019.07.001Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. Therefore, it remains uncertain as to whether an increased thrombotic risk may be expected by statin impact on lipoprotein(a) levels in COVID-19 patients. Further concerns are related to the observation that treatment with high-potency statins may be associated with an increased risk of incident type 2 diabetes, especially in obese patients [[54]Ahmadizar F. Ochoa-Rosales C. Glisic M. Franco O.H. Muka T. Stricker B.H. Associations of statin use with glycaemic traits and incident type 2 diabetes.Br J Clin Pharmacol. 2019; 85: 993-1002https://doi.org/10.1111/bcp.13898Crossref PubMed Scopus (28) Google Scholar]. Indeed, diabetes is a significant predictor of COVID-19 severe clinical manifestations. However, the risk of developing insulin resistance with initiation of statin therapy is relatively low according to available data [[55]Casula M. Mozzanica F. Scotti L. Tragni E. Pirillo A. Corrao G. et al.Statin use and risk of new-onset diabetes: a meta-analysis of observational studies.Nutr Metab Cardiovasc Dis. 2017; 27: 396-406https://doi.org/10.1016/j.numecd.2017.03.001Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar]. Therefore, whether statin-induced diabetes may be a reason to discourage statin use in COVID-19 patients is questionable. Finally, the benefit-risk balance of statin therapy should be carefully evaluated in older patients with COVID-19. Indeed, beyond being at higher risk of poor prognosis, these patients are also at higher risk of statin-related adverse effects [[56]Cholesterol Treatment Trialists' CollaborationEfficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials.Lancet. 2019; 393: 407-415https://doi.org/10.1016/S0140-6736(18)31942-1Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar]. Overall, available data and hypotheses based on biological plausibility do not support the notion that statin therapy may worsen the prognosis of patients with COVID-19. Conversely, they suggest that some clinical benefits in COVID-19 patients may derive from statin-mediated cholesterol-lowering and pleiotropic effects. To this regard, although no clinical studies are currently available clearly showing that statins can reduce the incidence of cardiovascular events in COVID-19 patients, evidence is emerging showing a possible benefit from statin therapy in reduction of COVID-19 severity and mortality. Therefore, the continuation of statin therapy in COVID-19 patients should be considered [[49]Banach M. Penson P.E. Fras Z. Vrablik M. Pella D. Reiner Ž. et al.Brief recommendations on the management of adult patients with familial hypercholesterolemia during the COVID-19 pandemic.Pharmacol Res. 2020; 158: 104891https://doi.org/10.1016/j.phrs.2020.104891Crossref PubMed Scopus (56) Google Scholar,[57]Khera A. Baum S.J. Gluckman T.J. Gulati M. Martin S.S. Michos E.D. et al.Continuity of care and outpatient management for patients with and at high risk for cardiovascular disease during the COVID-19 pandemic: a scientific statement from the American Society for Preventive Cardiology.Am J Prev Cardiol. 2020; 1: 100009https://doi.org/10.1016/j.ajpc.2020.100009Crossref PubMed Scopus (78) Google Scholar]. Further, despite a current lack of direct information in COVID-19 subjects, observational and interventional studies appear warranted to establish both the efficacy and safety of de novo initiation of statin therapy as add-on treatment for the management of COVID-19. AS, SG and VB conceived the study and designed the review. SG and VB wrote the first draft. AS, PEP, MP, MB and GFW critically revised the text. All authors approved the final version. MB has served on the speakers bureau of Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm, KRKA, MSD, Sanofi-Aventis, Servier and Valeant, and has served as a consultant to Abbott Vascular, Akcea, Amgen, Daichii Sankyo, Esperion, Lilly, MSD, Resverlogix, Sanofi-Aventis; Grants from Sanofi and Valeant; GFW has received honoraria for lectures and advisory boards for Sanofi, Regeneron, Kowa, and Amgen; PEP owns four shares in Astra Zeneca PLC and has received travel/speaker's fees from Amgen Inc. The other authors have no competing interests to declare.
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